Sphingosine-1-phosphate (hereinafter referred to as “S1P”) is a physiologically active lipid which is produced upon metabolism, in cells, of sphingolipids typified by sphingomyelin. S1P is known to have wide varieties of actions, including a cell differentiation inducing action, a cell growth promoting action, control of cell motility, and an antiapoptotic action, and to show physiological actions such as angiogenesis, induction of bradycardia, activation of inflammatory cells, and activation of platelets (non-patent document 1).
Five subtypes, Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4), and Edg-8(S1P5), are reported as receptors of S1P (non-patent document 2).
One of them, Edg-1(S1P1), is expressed in large amounts in immune cells such as T cells and dendritic cells, and the vascular endothelial cells, and is suggested to contribute deeply to S1P-associated migration of T cells (non-patent document 3), migration of mast cells (non-patent document 4), emigration of T cells and B cells from lymph organs (non-patent document 5), and angiogenesis (non-patent document 6), and to be involved in autoimmune diseases such as Crohn disease, irritable colitis, Sjögren syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection reaction after organ transplantation, cancer, retinopathy, psoriasis, osteoarthrosis, and age-related macular degeneration.
Thus, Edg-1(S1P1) ligands are considered to be effective for the treatment or prevention of these diseases.
So far, certain types of thiophene derivatives (non-patent document 7), phosphate ester derivatives (patent document 1, patent document 2, non-patent document 8), and thiazolidine derivatives (patent document 3) have been reported as Edg-1(S1P1) ligands. However, inhibitors having structures similar to the structure of the compound of the present invention have not been known.
Compounds similar in structure to the compound of the present invention are marketed as reagents by Bionet, but their pharmaceutical uses are completely unknown.
Patent document 1: WO02/18395                Patent document 2: Japanese Unexamined Patent Publication No. 2003-137894        Patent document 3: Japanese Unexamined Patent Publication No. 2002-332278        Non-patent document 1: J Biol Chem. 2004, 279:20555, FASEB J 2002, 16:625, Proceedings of the Japanese Society of Immunology 2003, 33:2-J-W30-20-P        Non-patent document 2: Pharmacol Res 2003, 47:401        Non-patent document 3: FASEB J 2002, 16:1874        Non-patent document 4: J Exp Med 2004, 199:959        Non-patent document 5: Nature 2004, 427:355        Non-patent document 6: J Clin Invest 2000, 106:951, Biocchim Biophys Acta 2002, 1582:222        Non-patent document 7: J Biol Chem 2004, 279:13839        Non-patent document 8: Bioorg Med Chem Lett 2003, 13:3401        